The objective of this project is to develop new single photon emission computed tomography (SPECT) imaging agents for evaluating dopaminergic receptors of the central nervous system (CNS) in normal and disease states. In the past funding period, we have reported the first Tc-99m labeled dopamine transporter imaging agent ([99mTc]TRODAT-1). The first dopamine transporter imaging study of a Tc-99m labeled agent in human brain was reported from our group (Eur J Nucl Med 23:1527-1530, 1996). Based on this milestone achievement, we propose to focus on the development of Tc-99m labeled D2/D3 dopamine receptor imaging agents. Our objective is to test the hypothesis that it is feasible to prepare Tc-99m labeled "benzamide" derivatives with similar biological properties to those of [11C]raclopride and [123I]IBZM, the most commonly used D2/D3 dopamine receptor imaging agents. To test this hypothesis, a series of benzamide derivatives with chelating side groups will be prepared for complexing with Tc-99m. Specific aims include: 1) Synthesis of the proposed new ligands for radiolabeling. Four groups of benzamide derivatives containing an N2S2 chelating system for complexing TcO(IV) will be prepared. The chelating ligand system will form neutral and lipophilic [99mTc]TcON2S2 complexes, which can pass through the intact blood-brain barrier by a simple diffusion mechanism. The structure-activity relationship of the proposed benzamides will be evaluated. 2) Studies of radiochemistry for preparation of Tc-99m, Tc-99 and Re labeled target molecules. 3) Evaluation or biodistribution in rats and in vitro autoradiography as well as in vitro receptor binding study. 4) In vivo SPECT imaging studies in non-human primates. 5) Evaluation of in vivo metabolism and modeling. 6) Radiation dosimetry calculation and toxicology study. 7) Phase I clinical trial in humans. The proposed novel Tc-99m labeled D2/D3 dopamine receptor imaging agents, if successfully developed, can provide valuable tools for studying CNS dopamine receptors in vivo. It is likely that the Tc-99m based agents will be widely distributed and accepted as a routine procedure for differential diagnosis of patients with various CNS diseases, such as Huntington's, Alzheimer's and Parkinson's diseases. In addition, the D2/D3 dopamine receptor imaging agents may provide a novel method to study D2/D3 receptor occupancy, which may be critical in producing extrapyramidal side effects in schizophrenic patients undergoing neuroleptic treatment.